Epidemic louse borne typhus has historically caused massive mortality in the wake of war, famine, and great migrations.1 In the four years from 1918 in Eastern Europe and Russia there were up to 30 million cases, and three million deaths. In
the recent past in Burundi typhus has infected prison inmates before spreading to the wider community.2 It remains a risk among refugee populations in all parts of the world, despite its omission from a recent review of health
care in refugee camps.3

Tick borne typhus is a significant risk to human health, especially in the Eastern United States, Brazil, the Mediterranean
basin, the African veld, India, and Australia. Endemic flea borne typhus occurs sporadically wherever rats and man live closely
together. Scrub typhus is a hazard in many parts of South East Asia and beyond, and is the first of the rickettsial infections
to show evidence of resistance to standard antibiotics.4 No useful vaccines are currently available for any of the rickettsial infections.

Pathogenesis

The rickettsiaceae are a family of obligate intracellular small Gram negative coccobacilli which infect humans chiefly through
insect vectors, mostly from animal hosts, but sometimes by transovarial transmission in the insects themselves.5

The genus Rickettsia is divided into:

(1) R prowazekii, the agent of classical epidemic typhus, transmitted by the human body (clothing) louse,Pediculus humanus (but not by head lice) from active human cases or from healthy carriers or subclinical cases, so-called Brill-Zinsser disease.6 Typical circumstances were evident in the Burundi outbreak,2 which started in a prison at N'Gozi in 1995 and spread to the malnourished inhabitants of refugee camps in the central highlands
(over 1500 m), causing over 50 000 cases with a mortality of 2.6%. The infectious agent in the faeces of the body louse is
usually inoculated by scratching of the site of the louse bite, but in epidemics in closed communities an aerosol of dried
louse faeces may be inhaled. The genome of the organism has recently been sequenced, providing new evidence of an evolutionary
relationship between rickettsiae and intracellular mitochondria in general.7

(2) R mooseri (R typhi), the causal agent of endemic typhus, is carried by the rat fleaXenopsylla cheopis, and typically infects man in markets, grain stores, breweries, and garbage depots. It is often a mild illness, but can become
more aggressive in refugee camps, and a fatal case in the UK was infected in Spain.8

(3) The “spotted fever” group of rickettsiae, which contains a large number of species transmitted from rodents, dogs, and
wild animals by ticks:

(A) R rickettsii, the agent of Rocky Mountain spotted fever, so-called because of the area of its discovery, but now mainly occurring in the
eastern Atlantic states of USA, especially in trekkers and hunters exposed to wild animal ticks,9 and with the potential for a severe haemorrhagic illness.

(B) R conorii, the cause of tick typhus in the Mediterranean area and in India, which is transmitted by the brown dog tick Rhipicephalus sanguineus—the tick is brown, the dog not necessarily so. A recent human case in Lille in northern France was caused by a tick from
a dog imported from Marseille.10

(C) R africae, which is found in the African veld, is transmitted in game park areas by ticks living on cattle, hippo, and rhino.11

(D) R japonica, R australis, and a variety of other similar organisms, which are widely distributed in Asia and Australia,1213 and infect man through various species of animal ticks.

(4) R tsutsugamushi, recently renamed as a new genus with only one species, Orientia tsutsugamushi,14 the agent of scrub typhus, acquired from the bite of larval trombiculid mites living on the waist high Imperata grass growing in previously cleared jungle around villages and in plantations. The area of risk includes South East Asia,
the Indian subcontinent, Sri Lanka, and other Indian Ocean islands, Papua New Guinea, and North Queensland.

The rickettsial fevers are acute bacteraemic illnesses characterised by headache, mental confusion (and, in severe cases,
meningoencephalitis), a macular rash, mainly on the trunk, with, in some types, a small black scab or eschar at the site of
the insect bite, with local or general lymphadenopathy.

Rickettsial proliferation on the endothelium of small blood vessels releases cytokines which damage endothelial integrity,
with consequent fluid leakage, platelet aggregation, and polymorph and monocyte proliferation, leading to focal occlusive
endangiitis, causing microinfarctions, as in the typical “typhus nodule” of Wolhbach.15 This process especially affects the brain, cardiac and skeletal muscle, the skin, lungs and kidneys, and may cause venous
thrombosis and peripheral gangrene.

Clinical presentations

The incubation period of all rickettsial infections is 12 to 15 days on average, but can extend up to 28 days.

Murine and milder cases of scrub typhus often present as non-specific fevers for a few days' duration,16 with a minimal macular rash, or no rash at all, and no eschar at the site of entry. Generalised lymphadenopathy was a characteristic
feature of the milder cases seen in US soldiers in Vietnam, where tetracycline was freely prescribed for cases of “pyrexia
of unknown origin” and the specific diagnosis was made serologically in retrospect.

Learning points

The types of typhus fever are:

(A)

Epidemic louse borne:R prowazekii

(B)

Endemic flea borne:R typhi/R mooseri

(C)

Tick borne “spotted fever”: R rickettsii, R conorii, etc

(D)

Mite borne scrub typhus: O tsutsugamushi

The typhus fevers all present with headache and a macular rash. A clinical diagnosis is often made, and a specific therapeutic
trial undertaken, before serological confirmation is received.

Careful examination of the patient for the entry site eschar (insect bite) is helpful in the diagnosis of scrub and tick typhus,
the commonest types in travellers.

In Thailand there is evidence of resistance of scrub typhus to chloramphenicol and tetracycline. Possible alternative treatments
include rifampicin and ciprofloxacin.

Louse borne typhus epidemics are a risk in all refugee camps, especially in the cooler mountainous regions of tropical countries,
but also in European settings.

Foci of scrub typhus in jungle areas of South East Asia are maintained by vertical transmission in the mite vectors without
the need for mammal hosts.

Rocky Mountain spotted fever is a potentially serious febrile illness with a haemorrhagic rash and the possibility of diffuse
intravascular coagulation and acute renal failure. Perhaps surprisingly there is no eschar at the site of the tick bite, although
this is seen with the same organism in Brazil. Tick typhus in the Old World, with its many species types, varies in severity
but can cause hepatorenal failure. The rash is macular and there is an eshcar (“tache noire”) at the entry site in the majority
of cases. Mediterranean tick typhus (“fièvre bouttonneuse”) is the type most likely to be imported into the UK but only a
handful of cases are reported annually.

Scrub typhus is clinically similar to Old World tick typhus, with an eschar in up to 80% of cases, typically in the groin
or axilla (see fig 1), and the potential for an acute brain syndrome which can progress to coma and, rarely, death. Occasional imported cases
are reported in the UK.

The clinical severity of epidemic typhus is largely determined by the nutritional state of the population infected and in
the most extreme situations of malnutrition, such as in the concentration camps at Bergen-Belsen in 1945, a mortality of 50%
and upwards may occur. After an incubation period of about 14 days, there is a sudden onset of high prostrating fever with
severe headache, limb pains, and vomiting. The face is suffused and the victim appears vacant and semimute, with epistaxis
and a dry cough. The classical rash appears on about the third day on the trunk (see fig 2) and proximal limbs, consisting of irregular pink macules, which darken and coalesce but are not haemorrhagic. Constipation
is usual and paralytic ileus may ensue. Splenomegaly and generalised lymphadenopathy are common. In severe cases a meningoencephalitic
syndrome develops, with meningism, tinnitus and hyperacusis, followed by deafness, dysphoria, agitation, and coma. Survivors
may have hemiparesis, acute transverse myelitis, or peripheral neuropathy. Other possible complications include: (1) secondary
bacterial infection, leading to bronchopneumonia, parotitis, or otitis media; (2) myocarditis, presenting as low output cardiac
failure or sudden collapse, typically when the generalised febrile illness is recovering; and (3) peripheral gangrene or venous
thromboembolism.

Diagnosis

Because of the lack of clues from routine laboratory investigations, which are usually normal, and the facts that rickettsiae
are dangerous pathogens and specific serological tests are only available from a few specialised laboratories, often in retrospect,
it is advisable to make a clinical diagnosis of the typhus fevers based on a detailed travel and occupational history and
the physical signs. In these circumstances a therapeutic trial of specific treatment is justified, as rapid defervescence
is strongly suggestive of a correct diagnosis.

The differential clinical diagnosis includes typhoid (enteric) fever, viral haemorrhagic fever, meningococcal infection, louse
borne relapsing fever, leptospirosis and, as for all fevers acquired in the tropics, malaria, which should always be excluded
by the examination of blood films.

Specific diagnosis can be made by:

(1) The Weil-Felix test, involving the demonstration of heterophile antibodies to strains of Proteus mirabilis(OX-19, OK-2, OX-K); this test is, however, negative in up to 50% of cases.

Management

Good general care of the patient is essential, emphasising fluid balance, oral toilet, analgesia, mild sedation if needed,
and appropriate antibiotics for secondary infections. Acute renal failure needs appropriate management and modification of
the antibiotic regimen.

Specific chemotherapy with chloramphenicol, first used in scrub typhus in 1947,18 is with 500 mg six hourly orally or intravenously for seven to 10 days in adults, or 12.5 mg/kg six hourly for children.
If tetracycline is preferred, the same dosages are used. In all mild to moderate cases, however, the treatment of choice is
oral doxycycline 200 mg for adults, 100 mg for children, in a single dose, with one further dose in five to seven days if
relapse of fever occurs.

There are now reliable reports4 of partial resistance to chloramphenicol and tetracycline, for O tsutsagamushi only, in northern Thailand. Both are bacteriostatic agents so that in cases acquired there it may be wise to treat scrub
typhus ab initio with rifampicin or a quinolone antibiotic, for example ciprofloxacin.

Multiple choice questions (answers at end of paper)

1.

Scrub typhus in South East Asia is transmitted by:

(A)

Ticks from wild animals

(B)

Rat fleas

(C)

Larval mites on long grass

(D)

Head lice

(E)

Sandflies

2.

Epidemic louse borne typhus:

(A)

Typically has a haemorrhagic rash and evidence of diffuse intravascular coagulation

(B)

In tropical countries occurs most in seaside areas of high temperature and humidity

(C)

In undernourished refugees is likely to carry a high mortality if untreated

(D)

Can lead to peripheral gangrene and loss of digits in severe cases

(E)

Should be controlled by the widespread prescription of ciprofloxacin in the community at risk

Prevention and control

In epidemics of louse borne typhus it is essential to treat all cases with doxycycline, and indeed to consider mass prophylaxis
with this agent in the whole population at risk and for carers and medical workers on a weekly basis. All those at risk should
initially be issued with clean clothes, which are dusted with powder containing 1% malathion or 1% permethrin. Again, this
should include medical attendants, since history shows that they are at high risk.

Endemic flea borne typhus can be controlled by antirodent measures, and individual use of insect repellent creams.

Measures to reduce the risk of tick typhus include the control of dog ticks, “buddy” inspection for ticks after visits to
game parks or forests, insect repellents, and the impregnation of clothing with DEET (diethyl toluamide) or permethrin.

Scrub typhus control depends on the clearing of secondary jungle grass within and near villages, and, in travellers, the use
of jungle boots and gaiters with long trousers, permethrin or DEET impregnation of clothing, and consideration of the use
of prophylactic oral doxycycline 200 mg weekly in those who have to travel through areas of known high risk, for example soldiers,
policemen, plantation workers.